An exhaustive and careful look at blood samples of people with chronic fatigue syndrome found no sign of the murine retrovirus XMRV, according to Ila Singh, MD, PhD, and colleagues at the University of Utah in Salt Lake City.

The immediate implication is that people with the debilitating condition should not be taking anti-retroviral drugs, as some began doing since the link was proposed, Singh and colleagues argued online in the Journal of Virology.

Virologist John Coffin, PhD, of Tufts University in Boston, who was not involved in the study, told MedPage Today the Singh study is almost the last word on the issue.

"It's fair to say that there is very little wiggle room left," Coffin wrote in an email.

But Coffin noted that other studies on the connection, which are currently under way, should report soon. "We should have a very clear picture by the end of the year, if not before," he said.

The possibility of a link between the disease and the proposed pathogen – formally known as xenotropic murine leukemia virus-related virus – arose in 2009, when Science published a study that reported the DNA from XMRV in 68% of sampled patients. A second study appeared soon after to confirm the finding.

But several research teams subsequently have been unable to find the retrovirus in patients with chronic fatigue syndrome.

There have also been suggestions XMRV might play a role in prostate cancer.

The studies that have found a link had flaws that might have created a spurious association, Singh and colleagues argued. For instance, patients and controls were selected from different geographical regions; control groups were often small; and in most cases investigators were not blinded to the identity of samples.

Studies that did not find a link also had flaws including a lack of adequate controls, they noted.

To overcome those hurdles, Singh and colleagues studied 105 chronic fatigue syndrome patients and 200 healthy controls, all from the Salt Lake City area.

They also obtained and studied new blood samples from 14 of the participants in the 2009 study, who were all positive for XMRV in tests conducted by the original researchers.

All samples were processed in a blinded fashion, the researchers reported, and those from the Salt Lake City participants were collected within a period of three weeks, to avoid time gaps that have plagued some previous research.

They attempted to detect XMRV DNA by using four different polymerase chain reaction ( PCR ) assays, all of which had been used in previous studies. They tested for antibodies to XMRV using two methods and, in a subset of samples, attempted to culture the virus. They found:

•The blood of both patients and controls was always negative for XMRV DNA.•There was no difference between patients and controls in their reaction to a recombinant XMRV protein used to test for antibodies.•They were unable to grow XMRV in culture from a subset of 65 samples.•There was evidence that mouse DNA, which might be expected to incorporate XMRV genetic material, was a contaminant in some of the PCR assays used in previous studies.•Testing the new samples from the 2009 study participants found no genetic material from XMRV or antibodies to the virus.

Interestingly, Singh and colleagues initially found some samples to be positive for the virus, as well as in some negative controls.

It turned out that a robotic analyzer had been contaminated some months before with mouse DNA, they reported. When they repeated the testing manually, they found no sign of XMRV in the same samples.

"Our experience has taught us that the detection of XMRV in blood is fraught with difficulties," the authors commented.

Tufts virologist Coffin said the research "looks like a very carefully done study" that is very close to replicating the original experiments, but with markedly different results.

He noted that the evidence for XMRV infection "rests on five legs," specifically the detection of:

•Infected cells and integration junctions in vivo, which has only been shown in prostate cancer patients.•Viral antigens on cells from patients.•Antibodies against XMRV in samples from chronic fatigue syndrome patients.•Virus-like sequences, again in samples from chronic fatigue syndrome patients.•And isolation of infectious virus.

Of those, he said, all but the first have been challenged, "in the almost complete absence of credible confirmatory findings."

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